ABPD: An optimized retinoid with RAR-dependent and independent activity

The retinoids play a key role in differentiation, proliferation and apoptosis and as a result over 30 naturally occurring and synthetic analogs of retinoic acid are now either in development or on the market. The focus of retinoid attention has been skin conditions and cancer, however although efficacy has been demonstrated in acute promyelocytic leukemia and various skin cancers, the extension of therapeutic benefit to other cancers has been limited. In our recent dossier “Retinoids: An A-Z guide to their biology, therapeutic opportunities & pharmaceutical development” (click here for access) we set out to offer a full and up to date insight into the complexities of the retinoids. Furthermore we describe how these complexities relate to the limited therapeutic potential of the retinoids and strategies for overcoming these limitations.

Upon entry into cells, retinoids are converted to alltrans retinoic acid (tRA) and 9-cis RA, physiologic metabolites that translocate to the nucleus where they bind to retinoic acid receptor (RAR) and retinoid X receptor (RXR), respectively. Ligand-bound receptors then associate with cis-acting RA response elements (RARE), located in the regulatory regions of target genes, and activate gene transcription. The complex actions of RAR and RXR isotypes mediate multiple retinoid effects by forming either homo- or heterodimers. In addition to receptor activation, RA can also interfere with the transactivation function of activation protein-1 (AP-1). AP-1 is involved in cell proliferation and transformation, as well as tumor invasion, probably by regulating the expression of various matrix metalloproteinases.

Retinoids have been extensively evaluated as potent chemoprevention and chemotherapeutic agents. The potential of the retinoids to prevent breast cancer was noted almost 20 years ago. Over this time period retinoids have demonstrated therapeutic efficacy, albeit variable, in a number of other cancers. One retinoid that has attracted particular attention is 4-HPR (retinamide; fenretinide). Initial preclinical studies indicated that 4-HPR can suppress carcinogen-induced cancers in rats; subsequent phase III trials demonstrated that 4-HPR can prevent second breast malignancies in premenopausal women with early breast cancer. In contrast 4-HPR is ineffective in patients with advanced disease and this may mirror the epigenetic silencing of RAR receptors. In addition to breast cancer, 4-HPR has been in development for the treatment and/or prevention of prostate cancer and CNS cancers.

Like 4-HPR, CD437 binds to RARgamma receptors, although both molecules induce significant apoptosis in a variety of cancer cell types by mechanisms that are independent of RAR activation. Although 4-HPR has demonstrated clinical efficacy, poor pharmacokinetics, reversibility, and drug resistance may all contribute to the variable and sometimes limited extent of this efficacy. Korean researchers have therefore synthesized a mini library of retinoid derivatives based on the structure of 4-HPR.

In their recent International Journal of Cancer article this group report that the lead molecule from this series, ABPN/CBG41 was substantially more active that 4-HPR with respect to the inhibition of proliferation in a wide variety of cancer cell types. Further investigation revealed that ABPN induced apoptosis in a representative cell line, the colon cancer line, HCT116. Apoptosis was related to PARP cleavage by caspase-3 and caspase-8, and non-selective binding to RAR receptors and/or suppression of AP-1 activity. This combination of pro-apoptotic activity and AP-1 suppression suggests that ABPN may both kill cancer cells and also limit their invasive properties.

The field of histone deacetylation continues to receive considerable interest due to the ability of histone deacetylase (HDAC) inhibitors to modulate transcriptional activity. Molecules from this therapeutic class can induce cell cycle arrest, differentiation and apoptosis and therefore have the potential to occupy an indomitable position in the fast-moving cytostatic market. In response to the emergence of HDAC inhibitors as a major therapeutic class in the fight against cancer LeadDiscovery recently published one of the most comprehensive overview of the pharmaceutical potential of HDAC inhibitors (click here to access "Histone deacetylase inhibitors: Redefining pharmaceutical approaches to the treatment of cancer"). One of the prototypic HDAC inhibitors is butyrate and it is intriguing that the butyryl group in ABPN contributes to its activity and furthermore, ABPN inhibits HDAC activity. One effect of HDAC inhibition is to reintroduce RAR expression to cancer cells and combining HDAC inhibition to reintroduce RAR expression and RAR receptor activation through its retinoid activity may explain in part the efficacy of ABPN. The rational optimization of both of these activities may lead to the identification of candidate of even greater therapeutic relevance.

Entry date Thursday, January 22, 2004

Adapted from Um et al, Int J Cancer. 2003 Dec 20; 107(6): 1038-46.